Improved methods for providing compositions for controlled release of therapeutic agents are disclosed and exemplified in applicants' above-mentioned parent application Serial No. 07/054,372, now U.S. Pat. No. 5,000,886. It has now been discovered that such novel compositions are uniquely suitable for treating dental diseases.
Drugs are conventionally administered orally or via injection, often at a site remote from the target. Over a relatively short period of time, the drug diffuses into the circulatory system of the patient and is distributed to the various organs and tissues, at least one of which is the intended target for the drug. The action of the drug on organs other than the target may result in undesirable side effects. Finally, the drug is metabolized or otherwise reversibly removed from the organism by excretion or chemical deactivation. When drugs are delivered orally or by injection by conventional, nonsustained release formulations the level and duration of availability of the drug cannot be controlled independently; only the size and frequency of the dose can be manipulated. Typically, there is an initially high concentration of available drug at the site of injection or in the circulatory system which then decreases gradually as the drug is distributed and consumed within the body of the patient.
In controlled or sustained delivery, a formulation of drug and a carrier is generally administered to the patient by ingestion or implantation. The carrier forms a drug reservoir that protects the stored drug from extraneous removal mechanisms and releases the drug to the biological reservoir at a predetermined rate. Controlled, sustained delivery of a drug prevents undesirable peaking of blood levels and makes the drug available at an optimum and substantially uniform concentration over an extended period of time. Only the released drug is subject to removal via metabolism and excretion. In the controlled sustained delivery method, there is potential for control of the drug release rate by factors inherent in the delivery package itself. Some of these inherent factors, such as the rate of hydrolysis of an absorbable polymer, or the rate of transdermal diffusion are in contrast to the externalized controls associated with classical delivery methods, e.g., rate of tablet intake, frequency of injections, etc. In accordance with prior methods, the maintanance of therapeutic blood levels of an antibiotic, for example, requires a fairly precise dosing of tablets. Though this may be uncomplicated for many adults, it may be difficult where gastric problems are present or for infants, the very infirm, or in veterinary work, such as with range animals.
The present invention provides a therapeutic composition which releases and maintains effective and predictable drug levels, thus eliminating the need for continual external supervision.
Known methods for controlled release of drugs to treat dental disease include the antibiotic-containing fibers described in Goodson, U.S. Pat. No. 4,175,326. The fibers are difficult to pack into the periodontal pocket and contact with the involved tissues may not be complete.
Baker, European Patent Application No. 0,244,118, describes therapeutic agent-containing microparticles suspended in a liquid carrier, but when placed into the periodontal pocket they wash out, and do not swell or stick to the involved tissues.
The dry microparticles of the present invention comprise a core material surrounded by a coating or encapsulating substance which is normally a polymer. Upon contact with moisture, these become tacky and adhere to the involved tissue and provide long term therapeutic effectiveness. Microparticles may consist of one or more core particles surrounded by a coating, or the microencapsulated substance may exist as one or more irregularly shaped particles surrounded by a coating which may have spherical form, or the exterior of the microparticles may be irregular in shape. The aspect ratio of the microparticles should be less than about 3.
In general, microparticles are produced to provide protection for the core material and/or to control the rate of release of the core material to the surrounding environment. Also included within the term "microparticles" are those in which the pharmaceutical agent is present as a solid solution in the coating, and may be present at one or more points or portions of the surface of the microparticles. The terms microcapsules and microspheres have also been applied to the above-named microparticles.
As suggested by Beck et al., U.S. Pat. No. 4,585,651, which discloses pharmaceutical compositions comprising microparticles of a pharmaceutical agent incorporated in a biocompatible and biodegradable matrix material, the methods for preparation of microparticles may be classified in three principal types:
(1) phase separation methods including aqueous and organic phase separation processes, melt dispersion and spray drying;
(2) interfacial reactions including interfacial polymerization, in situ polymerization and chemical vapor depositions; and
(3) physical methods, including fluidized bed spray coating, electrostatic coating and physical vapor deposition. The preferred method for this invention is (1).
Kent et al., European Patent Publication Number 052,510 disclose the microencapsulation of water soluble polypeptides in biocompatible, biodegradable polymers such as Poly(lactide-co-dl-glycolide)copolymers, also by a phase separation process utilizing an alkane solvent, and specifically exemplifies heptane as a hardening solvent.
The prior art hardening agents including hexane, heptane, cyclohexane and other alkane solvents leave substantial amounts of hardening agent residues in the microparticles. Tests have shown that heptane hardened microparticles typically contain 5-15% by weight of heptane. Since hardening agents can ultimately be released, low toxicity is of paramount importance for hardening agents used to produce microparticles for pharmaceutical applications, and it would be advantageous to provide the same.
In addition, a further drawback in use of hydrocarbon hardening agents of the prior art is that they are flammable and therefore require the use of explosion-proof facilities for manufacturing microparticles.
In the above-mentioned patent application Ser. No. 07/054,372, now U.S. Pat. No. 5,000,886, it is discloser that if volatile silicone fluids are used as hardening agents, the drawbacks of the prior art are overcome because of their very low toxicity and non-flammability characteristics. Microparticles produced by the phase separation microencapsulation process are different and better than those of the prior art because the residual hardening agent content is very low, e.g., on the order of less than 3 wt. %, preferably less than 1 wt. %. The results obtained therein were surprising because, while the coating material solvent is readily removable by vacuum drying, it had been the experience that residual prior art hardening agents, once incorporated into microparticles, are not readily removed by drying because they are, by nature, not soluble in the coating material and therefore do not permeate through the coating material.
Volatile silicone fluids are unique because these fluids essentially are not incorporated into the microparticles during the hardening step.
Despite the existence of the above-described sustained release compositions, a need still exists for a biodegradable sustained release composition which is capable of delivering a therapeutic agent for a period of time sufficient to treat a periodontal infection. Such a need is met now by providing dry, discrete microparticles having a hardening agent content of less than about 3% by weight and administering them directly to the periodontal pocket(s) of patients in need of treatment.